Project Summary With 36 million people currently living with HIV worldwide, developing a prophylactic HIV vaccine that protects against sexual transmission remains a top global health priority. A pre-clinical HIV vaccine approach based on strain 68-1 of rhesus cytomegalovirus expressing SIV antigens (RhCMV/SIV) elicits cellular unique unconventionally MHC-restricted T cell responses that are able to stringently control and ultimately clear pathogenic SIV replication in ~50% of vaccinated rhesus macaques (RM). However, it remains unknown if the 68-1 RhCMV-induced unique immunity and protection from SIV is a RM-specific phenomenon. To investigate this question as a means to successfully translation RhCMV into the clinic as an HIV vaccine, we will recapitulate these results using a Mauritian cynomolgus macaques (MCM), a nonhuman primate species with unique MHC genetics that reflect human immunogenetics. In specific aim 1, we will characterize the cellular immune response engendered in MCM vaccinated with CyCMV/SIV vaccine vectors. In specific aim 2, we will measure the ability of CyCMV/SIV to protect MCM from pathogenic SIV replication following low dose challenge. In specific aim 3, we will examine whole blood RNA transcriptomic profiles to identify correlates of immune protection. Successful completion of these studies will further our understanding of the unique protection afforded by CMV vectors and facilitate successful clinical translation of CMV as a prophylactic HIV vaccine.